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Phosphoinositide 3-Kinase δ Gene Mutation Predisposes to Respiratory Infection and Airway Damage

Lookup NU author(s): Dr Mario Abinun, Professor Andrew Cant


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Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-delta syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110 delta protein, the catalytic subunit of phosphoinositide 3-kinase delta (PI3K delta), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110 delta. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110 delta inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.

Publication metadata

Author(s): Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu CX, Blake-Palmer K, Perisic O, Smyth D, Maes M, Fiddler C, Juss J, Cilliers D, Markelj G, Chandra A, Farmer G, Kielkowska A, Clark J, Kracker S, Debre M, Picard C, Pellier I, Jabado N, Morris JA, Barcenas-Morales G, Fischer A, Stephens L, Hawkins P, Barrett JC, Abinun M, Clatworthy M, Durandy A, Doffinger R, Chilvers ER, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe A, Nejentsev S

Publication type: Article

Publication status: Published

Journal: Science

Year: 2013

Volume: 342

Issue: 6160

Pages: 866-871

Print publication date: 15/11/2013

Online publication date: 17/10/2013

Acceptance date: 23/09/2013

ISSN (print): 0036-8075

ISSN (electronic): 1095-9203

Publisher: American Assocation for the Advancement of Science


DOI: 10.1126/science.1243292


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Funder referenceFunder name
Association Contre Le Cancer
British Lung Foundation
Institut National de la Sante et de la Recherche Medicale
Karus Therapeutics Ltd
National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
Wellcome Trust
Medical Research Council UK
National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
2010-CSRDAgence Nationale de la Recherche
261441European Union (EU)
275880European Commission
260477European Research Council (ERC)
BB/J004456/1Biotechnology and Biological Sciences Research Council
PA00P3_134202Swiss National Science Foundation
U105184308Medical Research Council